Method for short-term and long-term drug dosimetry

ABSTRACT

Methods for the treatment of interferon-response disorders by administration of an interferon alone or in combination with adjunctive therapy are described. The invention encompasses providing to a patient both a formulation of an interferon that is suitable for short-term administration and a formulation of an interferon associated with a sustained release delivery system that is suitable for long-term administration. A principal advantage of the method is that responsiveness to treatment can be ascertained with short-term dosimetric techniques using one formulation of an interferon, which permits the appropriate selection of a dose that is both effective and safe for long-term administration using the second formulation.

CROSS-REFERENCE

This application claims benefit under 35 U.S.C. § 119(e) of U.S.provisional application 06/245,883 filed Nov. 3, 2000. The provisionalapplication is incorporated herein in its entirety.

FIELD OF THE INVENTION

This invention relates to a method and a kit for treating disorders,especially interferon-responsive disorders in warm-blooded animals and amethod for individualizing doses of a drug, e.g. an interferon, intreating such disorders. It further relates to a method for preparing along-term dosage for treating such disorders.

BACKGROUND OF THE INVENTION

Introduction

Long-term delivery of drugs using a device that provides a constantdelivery of a drug over time has significant advantages over delivery ofa drug by regular injections or even oral delivery. One advantage isthat the patient may avoid “peak-related” adverse effects. Anotheradvantage is that the patient may avoid “trough-related” ineffectivetherapy. Another advantage is avoiding frequent and sometimes painfulinjections for drugs that can't be administered orally. However, onedisadvantage of long-term, constant-rate delivery of drugs is that therehas not been an easy way to adjust doses for an individual patient in agiven population of patients having a disease. For example, inpopulations with hepatitis C, individual patients will require differentdosage levels of drug for treatment depending on viral load, patient ageand size, etc. The use of interferons is illustrative.

Interferons

The interferons are a group of endogenous proteins produced in responseto a number of infectious, proliferative or immunological disorders.Endogenous interferons have antiviral, immunomodulatory, orantiproliferative activities. The alpha and beta interferons are knownas type I interferons because these molecules appear to bind to a commonreceptor, the so-called α-β receptor. Exogenous interferons, such asrecombinant alpha (of various subtypes) or recombinant consensusinterferon, have been demonstrated to be useful in the treatment of, forexample, viral hepatitis C and certain cancers. A small percentage ofpatients who are treated with alpha or consensus interferon for periodsof several months may no longer manifest positive blood tests forhepatitis C viral ribonucleic acid (HCV-RNA). Such treatment may involveonly monotherapy with the interferon, or the interferon may be combinedwith another adjunctive therapeutic agent. Certain cancers also maystabilize or shrink in size with interferon monotherapy or withcombination treatments. Exogenous beta interferon (of various subtypes)has been shown to be useful as monotherapy in the treatment of multiplesclerosis. Exogenous gamma interferon has been shown to be useful asmonotherapy in the treatment of chronic granulomatous disease and morerecently has been suggested to be useful in the treatment of certainpulmonary disorders. Certain interferons have been chemically modifiedby the addition of polyethylene glycol or polyethylene oxide polymers(pegylated interferon) and may have enhanced antiviral activity in vivoas a result. Other forms of interferon-like peptides have been createdusing techniques to modify genes.

Adjunctive Therapeutic Agents

Ribavirin is a small organic molecule which, among other activities isknown to inhibit inosine monophosphate dehydrogenase, has antiviral andimmunomodulatory activities. The addition of ribavirin to an alphainterferon, for example, may increase the long-term response rate inpatients with hepatitis C. Other inhibitors of inosine monophosphatedehydrogenase may also be useful as adjuncts to alpha interferon incertain clinical settings, as may other classes of adjunctive therapysuch as: interleukin-2, interleukin-2 analogs or derivatives, histamine,histamine analogs or derivatives; a monoclonal antibody or antibodies; apolyclonal antibody or antibodies; or any combination thereof.

Limitations of Interferon Treatment

These current antiviral therapeutics are, however, not withoutlimitations. For example, the long-term success rate in the treatment ofhepatitis C is estimated to be for: alpha interferon alone (≈10-15%);consensus interferon alone (≈10-15%); pegylated alpha interferon alone(≈20-25%); alpha interferon combined with ribavirin (≈30-40%); and alphainterferon plus a histamine-related compound (≈30-40%). There isevidence that treatment with the combination of alpha interferon andribavirin or histamine analogs may induce responses in patients whoappeared not to be fully responsive to alpha interferon alone. Consensusinterferon in high doses has been reported to induce responses inpatients who failed to achieve sustained results on lower doses of alphainterferon.

Resistance and Side Effects

In a large percentage of patients, however, there is no significantantiviral activity by either alpha or consensus interferon, whether ornot combined with another agent. The patients are said to exhibitprimary viral resistance. In addition, a significant fraction ofpatients whose disease does respond initially do not have a sustainedresponse after drug therapy has ceased. The patients are said to exhibitsecondary viral resistance. Among those patients who fail to respond toalpha interferon, the majority also fail to respond to subsequenttreatment with consensus interferon. The reasons for primary orsecondary resistance are not completely understood but may involvesignificant variations in blood levels of the interferon, thedevelopment of antibodies directed against the interferon, the geneticfeatures of the virus and/or the patient, or changes in the virus and/orthe patient.

Furthermore, not all patients can tolerate therapy with an interferon,whether alone or in combination with an adjunctive therapeutic agent,because of adverse side effects. Some side effects may be worsened bythe addition of ribavirin, interleukin-2, or other adjunctive therapiesnow in use or under development. Moreover, certain patients who havebeen characterized initially as “resistant” to alpha interferon appearto respond to alpha interferon when a second or subsequent course oftherapy is given, suggesting that the patient may have been inadequatelytreated during the earlier course of therapy or otherwise not trulyresistant. Patients failing alpha interferon who are subsequently“responsive” to consensus interferon may be in a similar category, i.e.,inadequately treated during the initial course of therapy. Inadequatetreatment can easily occur if the initial duration of treatment is toobrief or the dose for a particular patient is too low, leading tomisleading or false conclusions regarding viral resistance.

Problems with Short-Term Administration

In addition, whether used as monotherapies or as part of combinationtherapies, currently available injectable interferons are inconvenientfor patients to administer over a long period of time. The principalreason is the required frequency of injections, from one or more timesper day to once per week. The dose of a drug in a formulation intendedfor short-term usage and frequent administration can be rapidly changed.Nonetheless, there is still a significant risk of peaks in drugconcentration in blood or tissues (occurring immediately after or earlyin the dosing cycle) and troughs (occurring just before the next dose isto be administered).

This phenomenon can be particularly troublesome with an interferonformulated for short-term usage with frequent administrations required.With peak levels, there may be an increase the risk of troublesome sideeffects and with prolonged trough levels, there may be periods of timewhen there is little or no interferon activity is present in the bloodor tissues.

In summary, any formulation of an interferon intended for short-termusage is usually highly adjustable with respect to the dose of the drugbut also highly inconvenient for long-term administration.

Problems with Long-Term Administration

A sustained release preparation of an interferon with a depot formcapable of delivering a biologically active drug at a stable rate formany months, or a year or even longer, would have many potentialadvantages. There are many potential forms of a sustained releasepreparation including but not limited to: an implantable, non-erodibledevice with a reservoir capable of holding the drug isolated from thetissues and then releasing the drug at a controlled rate systemicallyinto the body, or locally into a single organ or site; an implantableerodible device or matrix with drug in or on the matrix capable ofsystemic or local delivery; a gel or other suspension containing thedrug capable of controlled-rate systemic or local delivery; an externalpump for IV delivery; a patch or other controlled-rate transdermaldelivery system. The drug may be delivered as the unmodified molecule orcoupled covalently or non-covalently to carriers, polymers, nonpolymersor other molecules, from which the original molecule is released in itsoriginal or still modified form. Those skilled in the arts willrecognize that there are many other forms of chronic controlled-ratedelivery systems that could be employed.

One of the potential advantages of any sustained release system would bethe avoidance of frequent and painful injections, thereby minimizing thepossibility that doses would be missed which could potentially lead toineffective therapy. Another advantage would be the potential formaintaining stable or even fixed rate of delivery of a drug systemicallyor locally, thereby minimizing the chances for “peak-related” adverseeffects and/or “trough-related” ineffective therapy.

There are also potentially significant disadvantages with any long-termdepot. Any such formulation would necessarily involve, relative to ashort-term daily or weekly dose, the administration of a relativelylarge and potentially very costly amount of drug. If there is occurrencein the patient of a severe side effect requiring an immediate reductionin the dose, such a reduction would be practically impossible or verydifficult with any long-term sustained release preparation that had beenimplanted or injected. For a mechanical device, an erodible matrix, or agel or other suspension it may be necessary to perform an invasiveprocedure to attempt to remove all or part of the administered drug. Forall except the use of a mechanical device or transdermal patch, in fact,which hold the drug intact within a reservoir physically isolated fromthe body, it might be impossible to remove all of the drug. Accordingly,while long term administration of an interferon offers many advantagesto a patient, any error in selecting the long-term dose level orlong-term drug delivery rate could have very adverse and costlyconsequences.

Moreover, for patients with certain diseases such as viral hepatitis C,it may be desirable to individualize the dose as much as possible.Historically, patients have been treated with a fixed amount ofinterferon per week and such amounts have been maintained at the fixedlevel for many weeks or months in the absence of supervening sideeffects that mandated a reduction in dosage. Short-term delivery of aninterferon offers the potential advantage of permitting doses to beadjusted readily, while long term administration of a fixed rate of drugdelivered from, for example, a reservoir permits no adjustment at all.

In summary, a formulation of a drug, such as an interferon, used with along term delivery system or device is highly convenient for ensuringstable delivery of drug, but is relatively or absolutely inflexible withregard to adjustment of the drug and potentially expensive or requiringinvasive procedures to reduce the amount or eliminate the drug from thebody altogether.

ADVANTAGES OF THE PRESENT INVENTION

I have now invented an approach that addresses the problems in the priorart in the long-term use of a drug, e.g. an interferon, for thetreatment of disease of warm-blooded animals that require long termadministration to treat the disease or condition, e.g. one that isinterferon-responsive.

My invention maximizes the probability of delivering an effective doseof a drug, such as an interferon, to a warm-blooded animal with, e.g. aninterferon-responsive disease or condition and further maximizes thechances of delivering a safe dose of the drug, such that the dose isminimally toxic and therefore tolerated by the recipient.

My invention further facilitates the selection of a safe, tolerated andeffective dosage of a drug, e.g. an interferon, to be delivered to awarm-blooded animal by a long-term delivery system and facilitatesdose-individualization of the drug for an individual patient in thesetting of long-term administration using a long-term delivery system.

My invention also minimizes or eliminates the need to alter the rate orchange the dose-rate of the drug once long-term dosing has commencedwith a long-term delivery system.

Further, in the event that dose- or rate-adjustment is required, myinvention aids in minimizing the negative impact on therapy and cost ofany such adjustment in dose or rate after the commencement of dosingwith a long-term delivery system.

My invention also provides for combination therapy using, for example,interferon and one or more non-interferon adjunctive therapeutic agentsor even a second, structurally distinct interferon.

SUMMARY OF THE INVENTION

One aspect of the invention is a method for the treatment of a disorder,e.g. an interferon-responsive disorder, in a warm-blooded animal. Themethod comprises administering at least one drug, e.g. an interferon,formulated for short-term use, adjusting the dosage of the short-termformulation to increase and preferably maximize therapeutic responsewhile simultaneously decreasing and preferably minimizing adverse sideeffects, and subsequently selecting a dosage to be administered with along-term delivery system and long-term formulation suitable for use inthe long-term delivery system. Thereafter the long-term dosage isdelivered with the long-term delivery system and, if necessary, thedosage is subsequently adjusted with the long-term formulation andlong-term delivery system to further maximize therapeutic response whilesimultaneously minimizing adverse side effects.

Another aspect of the invention is a method for individualizing a doseof a drug, such as an interferon, in the treatment of a disorder, e.g.an interferon-responsive disorder, in a warm-blooded animal. The methodallows a physician to establish a dosage for treating a specific patientfor his or her individual needs over the length of treatment. The methodcomprises administering at least one drug, e.g. an interferon,formulated for short-term use, adjusting the dosage with the short-termformulation to increase and preferably maximize therapeutic responsewhile simultaneously decreasing and preferably minimizing adverse sideeffects in a plurality of patients and determining the most commonlyidentified optimal dosage in a sufficiently large population of suchpatients to define this dosage as a unit dose. Subsequently, using along-term formulation and a long-term delivery system, at least oneunit-dose, optionally with one or more fractional unit doses, isadministered such that, in aggregate, the optimal dosage identifiedduring dosing with the short-term formulation can be approximated withthe unit-dose/fractional unit-dose combination using the long-termformulation and long-term delivery system. Thereafter, a dosage isselected and administered with a long-term formulation in the long-termdelivery system. The long-term dosage is administered via the long-termdelivery system and the dosage of the long-term formulation vialong-term delivery system is optionally adjusted to further maximizetherapeutic response while simultaneously minimizing adverse sideeffects.

Another aspect of the invention is a method of manufacturing a long-termdelivery system for delivering a drug over time. The method comprisespreparing a long-term delivery device designed for delivery of a drug ata specified constant rate over time, the rate being determined to be astandard dosage rate to treat a disease state in the patient treatableover time by the drug, and preparing a second long-term delivery devicedesigned for delivery of the same drug at a specified constant rate overtime, which rate is a fraction of the standard dosage rate of the firstdevice. Each device is suitable for presentation to a patient in needthereof alone or in combination, depending on the dosage rate orfractional dosage rate determined to be appropriate for the patient. Thepatient may then have a device delivering a standard dosage rate or somefraction lesser or greater than the standard dosage rate, depending onthe characteristics of the patient, e.g. age, gender, weight, physicalcondition, etc.

Still another aspect of this invention is a kit useful for delivery of aconstant amount of a drug thereof over time, wherein the amount of drugdelivered to an individual patient within a population can be adjustedto the patient's individual needs for treatment. The kit comprises (a)at least one long-term delivery device designed for delivery of a drugat a constant rate over time, the rate being determined to be a unitrate as a standard dosage to treat a disease state in a patient in thepopulation over time, and (b) at least one long-term delivery devicedesigned for delivery of the same drug at a relatively constant rateover time, which rate is a fraction of the standard dosage rate, whereineach device in the kit is suitable for presentation to a patient in needthereof alone or in combination with an identical device or the devicehaving a different delivery rate depending on the dosage rate determinedto be appropriate for the patient. Alternatively, the kit comprises atleast two long-term delivery devices designed for delivery of the samedrug at the same or different constant rates over time, for which eachrate is a fraction of the standard dosage rate, wherein each device inthe kit is suitable for presentation to a patient in need thereof alongor in combination with an identical device or the other device,depending on the dosage rate determined to be appropriate for thepatient.

The invention is particularly valuable for the administration of omegainterferon, but also encompasses the use of other drugs, e.g.interferons (or mixture thereof) that bind to and activate interferonreceptors in warm-blooded animals with an interferon-responsive diseaseor condition. The invention also encompasses combination therapies ofdrugs, such as an interferon, or mixture thereof, and one or morenon-interferons or even a second, structurally distinct interferon. Theinvention is particularly valuable for the administration of omegainterferon to treat hepatitis C.

The invention is also useful for the administration of any highly potentmolecule, e.g., cytokines, hormones, or congener or analog thereof, forwhich there are significant side effects that can be lessened and/orbenefits that can be increased by the appropriate selection of short andlong-term doses. The invention is particularly valuable for theadministration of: growth hormone to treat growth defects and injuriesto tissues; sex hormones such as luteinizing hormone or relatedreleasing factors such as luteinizing hormone releasing hormone to treatendocrine disorders or cancer.

The invention is not limited by the number of different formulations. Ifa relatively smaller amount of, for example, interferon (whose durationin the body is measured in hours to days) is delivered by a formulationthat can be used to assess the safety, tolerability, and efficacy of alarger amount of the same or different interferon delivered in the sameformulation (but whose duration in the body is measured in weeks ormonths because of the larger amount provided), the current inventionalso encompasses this differential use of a single formulation to effectboth short-term and long-term therapy. The larger amount will differfrom the smaller amount by a preferred factor of at least four, morepreferred at least twelve, and most preferred twenty-four or higher.

The therapeutic method of the present invention is amenable tointermittent or repeated use for the treatment of acute, chronic,remitting or relapsing diseases or conditions.

The therapeutic method of the present invention can be utilized if thereis little or no delay in transitioning from short- to long-term therapy(minutes to days) or if there is a delay in transitioning from short- tolong-term therapy (weeks to months). For example, short-term dosing withan interferon such as omega interferon could occur at a single doselevel during days 1-14 of therapy and, based on the information obtainedregarding signs, symptoms, and laboratory values during these first 14days, appropriate long-term therapy could begin on day 15.Alternatively, and again by way of example, short-term dosing couldoccur during days 1-14, followed by a second but different short-termdosing from days 15-28, and long-term therapy could begin on day 29. Inanother example, information regarding responsiveness and tolerabilityto a short-term formulation of an alpha or gamma interferon could beobtained during 1-12 months of prior treatment. During this 1-12 monthperiod, the dose of alpha or gamma could remain the same or be alteredaccording to patient response and adverse side effects. Thereafter, aperiod of indeterminate length without treatment could occur. Treatmentcould be halted for any of several reasons including incompletetherapeutic response or unacceptable adverse events. For example, then,a no-treatment period could also be of 1-12 months duration. Thereafter,but still based on the information obtained during the 1-12 months ofprior active treatment, therapy with a long-term dosing formulation ofthe same or a different interferon could begin.

Other aspects of the invention may be apparent to one of skill in theart upon further reading the following specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the change in HCV RNA levels versus time inindividual human subjects with chronic hepatitis C infection resistantto 3-12 months of treatment with alpha interferon with or withoutribavirin.

FIG. 2 is a graph showing that increasing doses of omega interferonproduce progressively larger viral clearance rates (response rate) inpatients with chronic hepatitis C infection who were previouslyuntreated with an interferon.

FIG. 3 is a graph showing the pharmacokinetics of omega interferon(plasma concentration vs. time) after a single dose of omega interferonin humans. The median half-life of absorption is 3.1 hours; the medianhalf-life of elimination is 11.4 hours.

FIG. 4 is a graph showing the calculated pharmacokinetic profile ofomega interferon with once daily (q 24 hour) and 4 times daily (q.6hour) dosing cycles, with the same total daily dose of 15 μg.

FIG. 5 is a depiction of one sequence of events in adjusting the doseusing the short-term formulation 1, selecting the dose level for usewith long-term formulation 2 and its associated long term deliverysystem. The period of transition can be of any duration.

DETAILED DESCRIPTION OF THE INVENTION

Method of Treatment

One aspect of the invention is a method for the treatment of a disorder,e.g. an interferon-responsive disorder, in a warm-blooded animal. Themethod comprises the following steps:

-   -   administering at least one drug, e.g. an interferon, formulated        for short-term use, adjusting the dosage of the short-term        formulation to improve the therapeutic index in a patient with a        disease or condition responsive to the drug, thereby achieving a        desirable therapeutic response with no, few or clinically        acceptable adverse side effects;    -   based on the clinical information gained during administration        of the short-term formulation, selecting the dosage to be        administered initially as a long-term formulation and selecting        the time at which the transition from short-term formulation to        long-term formulation occurs, and thereby retaining or further        enhancing therapeutic index    -   based on the clinical information gained during administration        of the short-term formulation, selecting the time at which the        transition from short-term formulation to long-term formulation        occurs, and thereby retaining or further enhancing therapeutic        index    -   thereafter adjusting the dosage of the long-term formulation,        preferably but not necessarily upwards, if and as required.

The method of the current invention has several benefits. Consider, forexample, the clinical setting in which a long-term delivery system isused with a drug that has the potential for serious toxicity, has thepotential for different or progressive toxicities over time, has anarrow or even no therapeutic window (i.e., the effective dose-range issimilar to or overlaps the toxic dose-range), is very expensive, or acombination of these factors. Currently, interferons are costly, have anarrow or no therapeutic window and can cause different toxicities overtime. Therefore, an interferon represents one such drug. For such drugs,the selection of dose or changes thereof should be made with great care.

The treatment of hepatitis with an interferon is an example of oneclinical setting in which an interferon-responsive disorder must betreated typically for several months to a year or longer. If ahealth-care provider begins treatment with a long-term delivery system,e.g., where weeks or months of treatment are possible with a singleadministration, then the selection of the long-term dose is of criticalimportance.

It is worth noting that the administration of an interferon forlong-term delivery will generally involve the delivery of drug at moreor less a fixed rate throughout the course of therapy if system start-upor shut-down effects, if any, are ignored. Long-term delivery systemssuch as gels or polymers, once injected or implanted, typically erode ordissolve at rates that cannot be changed without surgical intervention.Implantable pumps that cannot be externally programmed or adjusted tochange the rate of delivery would require replacement or removal toeffect a dose change.

Consider the example where a long-term dose is selected and is effectivebut causes severe or serious side effects shortly after the initiationof treatment, e.g., after only a small percentage of the total dose isdelivered. Then, in order to protect the patient it may be necessary toremove part or all of the drug-delivery system in order to reduce thedose or dose-rate. Alternatively, consider the example where a long-termdose is selected and is effective and initially well tolerated but aserious or severe adverse effect appears later, but at a time when aclinically and economically meaningful percentage of drug still remainsin the system. Then, in order to protect the patient it may still benecessary to remove part or all of the drug-delivery system in order toreduce the dose or dose-rate.

Such removal may or will:

-   -   involve procedural risk, expense, and time for the patient    -   waste some or all of the (expensive) drug that had been        administered    -   reduce the chances for effective therapy    -   may induce the patient or health-are provider to abandon a        potentially convenient, safe and effective therapy.

Therefore, it is very desirable to avoid the early or otherwise risky orwasteful removal of the long-term delivery system. The method of thecurrent invention makes possible the achievement of this goal.

The benefits of the method of the current invention may be furtherexemplified. In the treatment of a disease or medical condition it isgenerally desirable to effect a therapeutic response as rapidly as issafely possible. This means that the onset of drug action isappropriately rapid. However, when a sufficiently severe adverse sideeffect occurs, the typical response is to stop administration of theoffending drug and to wait for the offset of drug action. Clearly, it isdesirable to have a rapid offset if a severe side effect occurs.Preferably the offset will be measured in minutes to a few hours.Examples of drugs with relatively rapid onset, possible severe sideeffect, but relatively rapid offset include the following drugsadministered by injection or infusion in a suitable short-termformulation include heparin that induces bleeding or penicillin thatinduces an allergic response.

Four examples of drugs administered by injection or infusion that haveless rapid offset (many hours to days or weeks) but are associated withserious side effects include cyclophosphamide and bone marrow cellulardepletion, cyclosporine and acute infection, interferons andgranulocytopenia, or interferons and depression or suicidal ideation.Any of these side effects may be sufficiently severe to put a patient'slife in jeopardy or to result in the death of a patient. In the presenceof such adverse side effects it may be necessary in these four clinicalsettings, respectively, to stop the offending drug and to administergranulocyte colony stimulating factor to increase cell count, toadminister antibiotics to combat infection, wait until granulocyte countreturns to normal before resuming treatment at a lower dose, or tohospitalize the patient and give antidepressants, electric shocktreatment or even maintain constant physical restraint.

In the case of an interferon dose that could deliver drug for weeks ormonths, the appearance of granulocytopenia can be rapid, occurringwithin a matter of a few days to weeks. Halting therapy or immediatelyreducing the dosage is necessary in order to reduce the risk of seriousinfection. An injectable form of interferon typically persists in thebody for several hours or, in the case of pegylated interferons, for aweek or more. In either case, the use of a short-term injectable can bemodified or halted immediately after granulocytopenia is detected.Recovery is typically rapid, within days, and therapy can be resumed orcontinued at a lower dose. However, if a multimonth form of theinterferon were present instead in the form of, for example, an injectedgel or polymer or implanted pump, then granulocytopenia would persist orworsen during continued presence of the drug—until and unless the gel,polymer, or pump is surgically excised or extracted. For the reasonsstated above, a sudden and unplanned removal of a long-term deliverysystem is very undesirable.

With the method of the present invention, the short-term formulation isadministered and adjusted until the desired therapeutic effect isachieved and, if adverse side effects occur acutely during a few days orweeks after beginning therapy, the dosage is lowered to reduce theseeffects. Then, and only then, the long-term dose is selected and thelong-term delivery system injected or implanted, thereby retaining thebenefits of the prior short-term dose selection.

In the case of an interferon dose that could deliver drug for weeks ormonths, the appearance of, for example, suicidal ideation after severalweeks or months of interferon therapy would constitute a medicalemergency. The method of the current invention can reduce this risk. Byapplying the method described herein, treatment with the short-termdosing form could be continued for many weeks or months in selectedpatients and after the risk of depression or suicidal ideation wasjudged to have passed or to be low, then an appropriately selectedlong-term dose can be administered.

Those skilled in the art will recognize other benefits of the currentinvention not described in the examples contained herein.

While the various aspects of this invention relate to the long-termdelivery of drugs generally, the details of the invention are explainedusing interferons, particularly omega interferon, as the drugs ofchoice. The term “interferon” (or “interferons”) is meant to beinterpreted in its broadest sense, i.e. glycoproteins that are potentcytokines, i.e. hormone-like low molecular weight proteins that regulatethe intensity and duration of immune responses and are involved incell-to-cell communications. The interferons possess complexanti-infective (e.g. antiviral), immunomodulating, and antiproliferativeactivity. Thus, the interferons are used for treating disorders of viralorigins, disorders of the immune systems, and disorders generallyreferred to as cancers, i.e. malignant neoplasms. These disorders arereferred to as “interferon-responsive disorders.” The types ofinterferon (“IFN”) include both naturally-occurring and recombinant IFN,e.g. alpha(alfa)-IFN, beta-IFN, gamma-IFN, tau-IFN, consensus IFN,leukocyte-IFN, omega-IFN, and the like. The term also includes amodified IFN such as one that is modified to include one or morepolyethylene glycol (“PEG”) molecules or a PEG-fatty acid moietyattached by covalent or non-covalent binding. Omega-IFN is preferred.

Typical suitable alpha interferons include recombinant interferonalpha-2b such as Intron-A interferon available from ScheringCorporation, Kenilworth, N.J., recombinant interferon alpha-2a such asRoferon interferon available from Hoffmann-La Roche, Nutley, N.J.,recombinant interferon alpha-2C such as Berofor alpha 2 interferonavailable from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield,Conn., interferon alpha-n1, a purified blend of natural alphainterferons such as Sumiferon available from Sumitomo, Japan or asWellferon interferon alpha-n1 (INS) available from the Glaxo-WellcomeLtd., London, Great Britain, or a consensus alpha interferon such asthose described in U.S. Pat. Nos. 4,897,471 and 4,695,623 and thespecific product available from Amgen, Inc., Newbury Park, Calif., orinterferon alpha-n3, a mixture of natural alpha interferons made byInterferon Sciences and available from the Purdue Frederick Co.,Norwalk, Conn., under the Alferon Tradename or alpha interferon analogssuch as described in U.S. Pat. Nos. 6,204,022 and 5,939,286.

The term “interferon beta” or “beta-interferon” or “β-IFN” means theproteins described in U.S. Pat. Nos. 4,820,638 and 5,795,779.

The term “interferon gamma” or “gamma interferon” or γ-IFN” means theproteins described in U.S. Pat. Nos. 4,727,138; 4,762,791; 4,845,196;4,929,554; 5,005,689;

5,574,137; 5,602,010; and 5,690,925.

The term “interferon tau” or “tau interferon” or “τ-IFN” means theproteins described in U.S. Pat. Nos. 5,939,286; and 6,204,022.

The term “interferon omega” or “omega interferon” or ω-IFN as usedherein means the species-specific protein that is described in U.S. Pat.Nos. 5,120,832 and 5,231,176. It can inhibit viral replication, cellularproliferation, and modulate immune response, even in settings orpatients where alpha interferon is not effective or has limitedeffectiveness. Omega-IFN is a naturally occurring interferon which haslimited homology to the alpha interferons (65%) and even less homologyto the beta interferons (35%), i.e., omega interferon is structurallydistinctive. Omega interferon appears to bind to what has been termedthe “α-β interferon receptor” as judged by in vitro testing. Usinggenetic engineering techniques, recombinant omega interferon ismanufactured in a form that is suitable for use in animals, includinghumans. It has been shown that antibodies developing in animals exposedto alpha interferon do not cross react with omega interferon, i.e., thatomega interferon is immunologically distinctive. Moreover, it has beendemonstrated in vitro in cells infected with the immunodeficiency virusthat the patterns of gene signaling induced by alpha and omegainterferon are different, i.e., that omega interferon is alsofunctionally distinctive.

The method may be used in any warm-blooded animal that has aninterferon-responsive disorder. The animals may be livestock, householdpets, or preferably humans. Thus, the method has both veterinary andhuman medicinal uses. Livestock treatable by this method include horses,cattle, swine, sheep, goats, and the like. Household pets include cats,dogs, rabbits, and the like. Preferably, however, the method of theinvention has its primary application in the treatment of humans, bothmale and female, young and old.

The diseases treatable by the method of this invention include those ofinfectious (e.g. viral), immunologic, or proliferative origins that insome portion of the population may be treatable by the administration ofan interferon. Diseases of viral origins are those caused by a virussuch as those set forth in Stedman's Medical Dictionary, 26^(th)Edition, particularly hepatitis B, C, or D, especially hepatitis C.Immunologic diseases are those of where the immune system of a patientis unbalanced. These diseases include, for example, chronicgranulomatous disease, acquired immunodeficiency syndrome, multiplesclerosis, systemic lupus erythematosus, and scleroderma. Proliferativediseases are generally those that include various types of malignantneoplasms, most of which invade surrounding tissues and may metastasizeto several sites. These are often referred to as cancers and include,e.g., condyloma accuminata, hairy cell leukemia, malignant melanoma,multiple myeloma, follicular lymphoma, non-Hodgkin's lymphoma, cutaneousT-Cell lymphoma, chronic myelogenous leukemia, basal cell carcinoma,carcinoid syndrome, superficial bladder cancer, renal cell cancer,colorectal cancer, laryngeal papillomatosis, actinic keratosis, or AID'srelated Kaposi's sarcoma. Other proliferative diseases include fibrosisof tissues or organs such as the lung or liver. Tuberculosis is alsotreatable by the method of this invention.

In carrying out the method of treatment of this invention, a drugformulated for short-term use is administered to a patient in needthereof and is adjusted to improve the therapeutic index. Thisadjustment may be done in one or a plurality of patients usingmeasurements well known in the art to show the drug is workingtherapeutically and whether there are known or suspected side effects.The term “short-term use” means that the drug is used as a formulationdesigned to be delivered to a patient multiple times to obtain thedesired effect. For example, the drug may be delivered by injections,infusion, implant, transdermally, orally, parenterally, or byinhalation. For example, an interferon may be delivered intravenously,intramuscularly, or subcutaneously once every 6 hours, 12 hours, or 24hours. Such dosing will generally show a concentration profile similarto that shown in FIG. 3. By changing the dosage frequency the amount inthe blood may change as shown in FIG. 4. The dosage used over the shortterm is then adjusted to maximize the therapeutic effect and minimizethe adverse side effects. The dosage has two components: the dose leveland the dose rate. The dose level is the total amount of drug deliveredto a patient, while the dose rate is the amount delivered to the patientper time unit.

For example, if omega interferon is administered by a standard route(e.g. IV, IM, subcutaneous), the following important parameters areuseful to maximize the therapeutic response while minimizing the adverseside effects and select a safe, tolerable, and effective dose forlong-term administration of omega interferon in patients with chronichepatitis C (“HCV”): number of target cells, rate constant for death oftarget cells, rate of production of target cells, fractional reductionin de novo rate of infection of target cells, rate constant for de novoinfection of target cells, viral load (i.e. HCV RNA levels), number ofproductively infected cells, rate constant for death of infected cells,fractional reduction in production of virions by infected cells, rate ofproduction of virions by infected cell, rate constant for clearance ofhepatitis C virions. These are described in more detail hereinafter.

Referring to FIG. 1, one sees a graph showing the change in HCV RNAlevels versus time in individual subjects with chronic HCV infectionresistant to 3-12 months of treatment with alpha-IFN, with or withoutRibavirin. Each patient was treated short-term for various periods oftime with 15 μg/dose of omega-IFN, with 3 doses per week on days 1, 3,and 5 of each 7 day week (both ordinate and abscissa linear scale) Threeof 8 patients manifested undetectable HCV RNA after treatment with omegainterferon. In resistant patients it appears that the maximal decreasein viral load may be apparent within the first few days of treatment,potentially as early as two days after the commencement of treatment.The tolerability and safety profile is reasonably well establishedwithin 4 weeks after beginning treatment.

In FIG. 2, a graph is presented that shows an increase in the responserate as measured by complete viral clearance in human patients withchronic HCV infection previously untreated with an interferon. Eachpatient was treated short-term for various periods of time with 15μg/dose of omega-IFN, with 7 doses per week for 2 weeks then 3 doses perweek on days 1, 3, and 5 of each 7 day week thereafter. The tolerabilityand safety profile is reasonably well established within 4 weeks afterbeginning treatment.

FIG. 3 presents a graph showing the pharmacokinetics of omega-IFN aftera short-term dose of omega-IFN in humans. The median half-life ofabsorption is 3.1 hours, while the median half-life of elimination is11.4 hours.

Turning now to FIG. 4, one sees a graph showing a calculatedpharmacokinetic profile of omega-IFN with once daily (q 24 hour) and 4times daily (q 6 hour) dosing cycles, with the same daily dose of 15 μg.With 4 times daily dosing the variation in omega plasma levels fromtrough (approximately 28.1 pg/mL) to peak (approximately 29.9 pg/mL) isapproximately 6% of the peak value. From the mid-range value ofapproximately 29 pg/mL, the variation to peak or to trough isapproximately 3%. Such a small variation is effectively a steady-stateand is achieved within 72 hours after the commencement of dosing withomega interferon. The variability can be reduced to even smaller valuesby reducing the dose and increasing the frequency of administration.This steady-state pattern effectively replicates that which would beobserved with a long-term delivery system emitting an interferon at afixed rate, where the rate was adjusted to achieve the plasma level asshown.

With the information shown in FIGS. 1-4 and other information, one canadjust the dosage of the short-term formulation to increase andpreferably maximize the therapeutic effect and decrease and preferablyminimize the adverse side effects and select a dosage to be deliveredover the long-term, i.e. from a month to a year or more, using along-term delivery formulation that delivers the drug at a controlledrate over time. While it may be desirable to commence long-term therapyimmediately upon cessation of short-term therapy, such immediatetransition is not always required and there may be a delay of days tomonths in commencing long-term therapy. In this method, the interferondelivered in the short term is generally the same as the interferon thatwill be delivered to the patients over the long-term, although aninterferon that differs from that given for the short-term may beadministered over the long term. Once a formulation for short-termadministration is established, the same, or essentially the sameformulation, may be used for long-term administration, albeit packagedfor long-term controlled releases. Alternatively, the long-termformulation may be different to account for the needed changes for thelonger, controlled-release characteristics. In some cases, if theattending physician believes it appropriate, more than one interferon oreven different interferons (e.g., alpha interferon and pegylated alphainterferon) may be used for the short-term or long-term administration,with each interferon being formulated the same or each formulateddifferently. If useful, the dosage can be adjusted upward byadministering a long-term formulation that provides a fraction of thedosage rate released by the first long-term formulation. Long-termformulations that are useful for delivering the desired dosage over timeinclude any formulations or devices that aid in the delivery of the drugin a controlled manner to the patient at the rate desired. Theseformulations may be internal (i.e. implantable in the patient to deliverthe drug internally) or external (i.e. delivers the drug internally withthe formulation located external such as a pump or chronic intravascularinfusion system or transdermal system) to the patient. While oral orinhalation devices may be used, they don't lend themselves to easylong-term use. If internal (implantable or injectable) the formulationmay be bioerodible, e.g., a gel or pellet, or nonbioerodible, e.g., amechanical device such as a pump.

An example of a suitable nonbioerodible formulation or device is oneemploying the DUROS® system (ALZA Corporation), which is a miniaturedrug-dispensing pump currently made principally from titanium and whichcan be as small as a wooden matchstick.

The DUROS® pump operates like a miniature syringe loaded with a druginside the drug reservoir. Through osmosis, water from the body isslowly drawn through a semipermeable membrane into the pump by a salt orother suitable osmotically active substance residing in the enginecompartment. This water is absorbed by the osmotic substance which thenswells and which slowly and continuously pushes a piston, dispensing thecorrect amount of drug out the drug reservoir and into the body. Theosmotic engine does not require batteries, switches or otherelectromechanical parts in order to operate. The amount of drugdelivered by the system is regulated by many factors, including, forexample, the materials used in manufacturing, the membrane's controlover the amount of water entering the pump, the strength of the osmoticagent, the frictional resistance to motion of the piston, the size andshape of the reservoir, the size, shape, and length of the orifice(s)through which the drug(s) exit the pump, the formulation and type of thedrug(s) and whether the formulation is a liquid, suspension, or gel, andpressures generated within the device to expel drug(s) orcounter-pressures generated in the tissues that resist such expulsion.

Other useful long-term delivery formulations may be prepared using theALZET® technology developed by the ALZA Corporation. These formulationsmay be delivered externally. The details of the ALZET technology may befound at www.alzet.com.

Patents that provide useful guidance in preparing long-term deliverydevices that may be useful in the methods and kits of this inventioninclude those which are assigned to Alkermes. Other patents includethose assigned to ALZA Corporation (now a subsidiary of Johnson andJohnson, Inc.), particularly relating to their “DUROS®” technology.Representative patents useful for the various aspects of this inventioninclude the following U.S. Pat. Nos. 5,529,914; 5,858,746; 6,113,938;6,129,761; 5,985,305; 5,728,396; 5,660,847; 5,112,614; 5,543,156;5,443,459; 5,413,572; 5,368,863; 5,324,280; 5,318,558; 5,221,278;4,976,966; 4,917,895; and 4,915,954. All are incorporated herein byreference.

The method of treatment, e.g. of HCV, can be further visualized withreference to FIG. 5. The figure is divided into a short-term formulationdosing period and a long-term formulation dosing period. During theshort-term formulation dosing period the dose level of omega interferonis adjusted to assess both initial antiviral response (shownhypothetically in the graphs of HCV RNA and liver enzymes over time)along with safety and tolerability. The IFN dose is adjusted to achievemaximal antiviral effects with acceptable safety and tolerability. Thisprocess is represented by the series of stepped boxes showing a maximumdose with a slight reduction. With the dose identified the patient isthen maintained on the dose during a transition, after which thelong-term formulation dosing takes places. The short-term formulation isdelivered first, and the long-term formulation is subsequently deliveredeither with or without an overlap of dosing with the short-term andlong-term formulations. If there is no overlap, the delivery of thelong-term formulation may be deferred for very brief periods of time(seconds to days) or longer periods of time (a week to several months).The long-term delivery is done with a long-term formulation and one ormore fractional modules (or several fractional modules). The patient ismonitored for the suppression of viral replication (as shown by thehypothetical graphs of HCV RNA and liver enzymes over time) as well asthe prevention of long-term adverse sequelae of HCV infection includingcirrhosis and liver cancer. The long-term treatment may be adjusted upwith another equipotent formulation or a fractional module dosage formor may be adjusted down by providing one or more fractional moduledosage forms after the device ends administration. Preferably acontrolled-release dosage per time unit selected for long-termformulation is about equivalent to the dosage release over a time unitfor the short-term formulation. For example, if the short-termadministration is 30 mg in 24 hours, then the long-term formulationwould be designed to release about 1.25 (30÷24=1¼) μg/hour. On the otherhand, the long-term dosage per unit of time may be more or less than theshort-term administration.

Individualizing Doses

Another aspect of the invention is a method for individualizing doses ofa drug delivered over an extended period of time to a patient in need ofsuch treatment. This is particularly valuable for patients receivingimplantable devices. The method is particularly useful for interferon,especially omega interferon. For example, the method comprisesdetermining the most commonly identified optimal dosage (i.e. thedose-level or dose-rate) in a sufficiently large population ofrecipients to define a unit dosage; and subsequently, using a long-termformulation for controlled release, administering at least oneunit-dosage optionally with one or more fractional unit dosages, suchthat, in aggregate, the optimal dosage identified during dosing with theshort-term formulation can be approximated with theunit-dosage/fractional unit-dosage combination using the long-termformulation. The desired dosage is selected for long term delivery andthereafter administered with the long-term delivery formulation, whichcan be optionally subsequently adjusted, if necessary, to furthermaximize therapeutic response with simultaneously minimizing adverseside effects. This is discussed further under “Dosimetry Protocol.” Theprinciples expressed in the Method of Treatment section apply the methodfor individualizing doses.

Convenient fractional unit-dose devices can be selected from 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9. Smaller or larger values less than1.0 can also be selected. With one unit-dose formulation and onefractional unit-dose module, e.g., 0.4, it is possible, by using one ortwo of these items, to attain doses of 0.4, 0.8, 1.0, 1.4 and 2.0unit-doses. With one unit-dose formulation and two fractional unit-dosemodules, e.g., 0.3 and 0.5, it is possible, by using one, two or threeof these systems, to attain doses of, e.g., 0.3, 0.5, 0.6, 0.8, 0.9,1.0, 1.1, 1.3, 1.5, 1.6, 1.8, 2.0, 2.3, 2.5, and 3.0 unit-doses. With anincrease in the number of available fractional unit-dose modules ofdiffering fractional values and/or an increase in the number of systemsthat can be utilized, it is possible to achieve any target number ofunit-doses. In this manner, it is possible to individualize the doseduring long-term therapy based on the results from the short-termtherapy period.

However, even if the short-term formulation and dosing-regimen matchingis not optimal when compared to that expected with the long-termformulation and long-term delivery system, the use of a first,short-term formulation, whether recently or in the past, willnonetheless facilitate recognition of useful antiviral effects (in thecase of hepatitis C) and the recognition of adverse effects that appearearly during the course of therapy with an interferon. It will also helpto prevent the premature selection of a dose or dose-rate with thelong-term delivery system that is too low to be effective or too high tobe safe and tolerated.

If the short-term formulation is delivered in such a manner that thedelivery characteristics match very closely those of the long-termformulation and attendant long-term delivery system, then the total doseper day, per week or per month (or for any other convenient unit oftime) found to be effective, safe, and tolerated using the short-termformulation, can be prepared for the long-term formulation. Thoseskilled in the art will recognize that this process of doseapproximation will apply to chemically modified or unmodified, andglycosylated or nonglycosylated (or both) interferons or otherinterferon-like proteins that have interferon activity.

Method of Manufacturing

Another aspect of the invention is a method of manufacturing a deliverysystem for delivering a drug, such as omega-IFN, over time in acontrolled manner. The method comprises preparing a long-term deliverydevice designed for delivery of a drug at a relatively constant rateover time, the rate being determined to be a standard dosage ratedesigned for a patient to receive a standard dosage amount over a unitof time to treat a disease state in the patient treatable over time bythe drug, and preparing a plurality long-term delivery system designedfor delivery of the drug at a relatively constant rate over time, whichrate for each module is a fraction of the standard dosage rate. Morethan one unit dose or more than one fractional dose may be selected.Each system is suitable for presentation to a patient in need thereofalone or in combination with an identical system or a long-termformulation delivering the standard dosage rate, depending on the dosagerate or fractional dosage rate determined to be appropriate for thepatient.

By way of specific example, a short-term formulation of omega interferonis administered to a patient with chronic HCV for one or two weeks. Theweekly dose may range from 22.5 to 360 μg. The patient is evaluated forthe presence of adverse symptoms, signs, or laboratory parameters. Thelevel of HCV RNA is also measured. Laboratory parameters will usuallyinclude a measure of the white blood cell count, along with a whiteblood cell differential, so that the number of granulocytes can bedetermined. If HCV RNA levels have declined, preferably to undetectablelevels, but the granulocyte count falls to less than 1000 cells/mm3,then the dose of omega interferon can be reduced by, for example,one-third or one-half. The HCV RNA level and granulocyte count are againmonitored and when the granulocyte count returns to, for example, atleast 2000 cells/mm³ and the HCV RNA level is judged to be stillsatisfactorily reduced, then the long-term dosing system is injected orimplanted without delay. The dose in the long-term delivery system isselected to suitably approximate the short-term dose previously shown tobe effective and acceptably safe.

By way of another specific example, a short-term formulation of omegainterferon is administered to a patient with chronic HCV for 4 months.There are no significant acute side effects and HCV RNA levels have beenreduced by more than 99.99%. After 4 months of treatment, the patientbecomes depressed. The depression is unresponsive to conventional oralantidepressants and the patient becomes suicidal. Omega interferon istemporarily stopped. The use of the short-term formulation facilitates amore rapid offset of action. The patient is hospitalized and receiveselectroshock therapy. Suicidal ideation ceases and depression remits.Omega interferon therapy is resumed at a lower dose using the short-termformulation. Depression does not reappear, HCV RNA levels are stillreduced (more than 99%) and 4-6 months afterwards the long-term deliverysystem is selected to suitably approximate the new, reduced dose nowshown to be effective and well tolerated.

By way of a third specific example, a patient with chronic HCV istreated for 6-12 months with a short-term dosing form of an alphainterferon (whether or not pegylated, with or without oral ribavirin).After one year of treatment with the alpha interferon regimen, HCV RNAlevels have been reduced by approximately 80% but are still detectable.Treatment with the alpha interferon regimen is halted. 1-12 monthslater, omega interferon is administered for two weeks using a short-termdosing form, and suitable laboratory and clinical tests are conducted todemonstrate viral responsiveness to therapy in the absence ofunacceptable acute side effects.

The system can be viewed then as a kit that can be used by the doctor orother provider of health care to individualize the dosage rate for apatient over time depending on the patient's characteristics such asage, gender, size, health condition, etc. The most commonly prescribeddose or dosage rate can be viewed as the median or “standard” or “unit”dosage. However, for a person who is physically of lower body mass thanthe median body mass for all patients, a the use of two deliverysystems, each giving about 40% of the “unit” dosage rate, may beappropriate, i.e. a total of 80%, while a person with a body masssubstantially higher than the median may require 140% of the unit dosagerate, e.g. a unit dose system plus a second system releasing at 40% ofthe unit dose rate.

The Kit

Still another aspect of this invention is a kit useful for delivery of arelatively constant amount of a drug thereof over time, wherein theamount of drug delivered to an individual patient within a populationcan be adjusted to the patient's individual needs for treatment. The kitcomprises at least one long-term delivery formulation designed fordelivery of a drug at a relatively constant rate over time, the ratebeing determined to be a unit rate as a standard dosage to treat adisease state in a patient in the population over time, and at least onelong-term delivery system or device designed for delivery of the samedrug at a relatively constant rate over time, which rate is a fractionof the standard dosage rate. Each formulation in the kit is suitable forpresentation to a patient in need thereof alone as a standard dosageformulation or a fractional amount thereof.

The kit can also comprise a combination of two or more identicalsystems, depending on the dosage rate determined to be appropriate forthe patient.

The kit can also comprise at least two or more long-term delivery devicedesigned for delivery of the same drug at the same or different (yetrelatively constant) rates over time, for which each rate is a fractionof the standard dosage rate, wherein each device in the kit is suitablefor presentation to a patient in need thereof alone or in combinationwith an identical module or the other standard device, depending on thedosage rate determined to be appropriate for the patient.

The kit can also comprise a combination of a short-term formulation witha delivery device or system therefor and one or more identical ordifferent long-term delivery systems containing the long-termformulation.

For example, different kits are shown in the table below: Short-termdosing form none 7 14 90 (number of days) Long-term dosing form 0.4 1.01.0 1.0 #1 (units) Long-term dosing form 0.4 none 1.0 0.1 #2 (units)Long-term dosing form none none none 0.1 #3 (units) total long-termunits 0.8 1.0 2.0 1.2

The examples in the table are non-limiting, and those skilled in the artwill recognize that other combinations are possible.

Both the method of manufacture and the kit aspects of the inventionpreferably will include a further refinement. This is the presence ofwritten dosing instructions. The dosing instructions are for adjustingthe rate of administration of the drug by employing one or a combinationof devices to achieve the desired release rate of the drug for anindividual patient depending on the patient's needs over time.

For example, in addition to the long-term dosing system(s) contained inthe kit, with or without short-term dosing systems, the kit may alsoinclude written dosing material may describe the use of omegainterferon, or other interferon, in an immunodiagnostic orimmunotherapeutic protocol to determine the appropriate short-term andlong-term dosing. Other factors to be considered in the protocolcomprise the medical disorder to be treated and, in the case of viralhepatitis C, the patient or viral factors that may affect responsivenessto an interferon, e.g., viral subtype and viral load as well ascharacteristics of the patient comprising age, sex, weight, height, raceor ethnicity, genetic profile comprising single nucleotide polymorphismsor haplotypes, the duration and severity of the medical disorder, thepresence and severity of hepatic injury, concomitant illnesses,concomitant medications and the like.

For example, written material can be applied directly to a container(such as by the application of a label directly to a vial containing theinterferon with or without carriers or excipients). Alternatively, acontainer-closure system holding the interferon can be placed into asecond container, such as a box, and the written material, in the formof a packaging insert, can be placed in the second container togetherwith the first container-closure system holding the interferon.

The written portion may describe indications for prescribing the drug,e.g., an interferon such as omega interferon, either as monotherapy oras part of combination therapy with one or more other interferons, withone or more non-interferons, or a combination or mixture of other drugs.Such indications would include an interferon-responsive disorder (forexample, viral hepatitis C). The written material should furtherdescribe that the interferon or other interferon, as monotherapy or partof a combination therapy regimen, is useful for the treatment of, forexample, viral hepatitis C.

In a preferred embodiment of this invention, the written material willdescribe omega interferon as the interferon to be used in treatment. Ina most preferred embodiment, the written material will describe thatomega interferon is used in the treatment of viral hepatitis, inparticular viral hepatitis C and viral hepatitis B.

In other embodiments, the written material may describe that theinterferon is of a recombinant form, manufactured in bacterial cells(and therefore usually nonglycosylated) or manufactured in mammaliancells (and therefore usually glycosylated). The written material willalso describe whether the interferon is chemically unmodified or hasbeen chemically modified by the addition of, for example, polyethyleneglycol moieties of various lengths and at various sites of attachment tothe interferon. The written material will also describe how toadminister the long-term formulation or module.

Still further, it can be described in the written material that theappropriate dose to establish the initial safety, tolerability, andefficacy profile of the short-term formulation is provided byadministering, on average, 1-210 μg per week of omega-IFN, and in a morepreferred embodiment 9-60 μg per week. The written materials willdescribe the protocol to be followed to adjust the initial dose inresponse to observed events relevant to safety, tolerability, andefficacy of the interferon. The written materials will also referenceone or more long-term delivery systems containing an interferon and theprotocol for selecting the dose or dose-rate to be delivered by saidlong-term delivery system containing or used with the related long-termformulation.

The written material would preferably be provided in the form requiredby the regulatory agency with jurisdiction over the approval formarketing of such an interferon, such as the United States Food and DrugAdministration, in the form of a package insert for a prescription drug.The written material would indicate that the interferon would beprescribed for use in patients having an interferon-responsive disorder.In a preferred embodiment, the written material would indicate that theinterferon is omega interferon and that the interferonresponsive-disorder is viral hepatitis, in particular viral hepatitis C.The written material would indicate that the interferon is useful asprimary or secondary treatment or in combination with other treatments.It would further describe that while the interferon has an effect on theinfected liver in patients with viral hepatitis C that the interferonalso may reach other tissues where it may have no therapeutic effect.

Principal toxicities could also be described and could include, by wayof example, headache, flu-like symptoms, pain, fever, asthenia, chills,infection, abdominal pain, chest pain, injection site reaction (asappropriate), malaise, hypersensitivity reaction, syncope,vasodilatation, hypotension, nausea, constipation, diarrhea, dyspepsia,anorexia, anemia, thrombocytopenia, leukopenia, other blood dyscrasias,myalgia, arthralgia, insomnia, dizziness, suicidal ideation, depression,impaired ability to concentrate mentally, amnesia, confusion,irritability, anxiety, nervousness, decreased libido, urticaria,alopecia, and others.

It may further be described in the written material that when symptomssuch as fever, chills, or flu-like manifestations are observed thatthese can be treated with Tylenol®, antihistamines such as Benadryl®,and that hypotension may respond to the administration of fluids orpressor agents or, if the symptoms or signs are sufficiently severe,that the dose should be reduced or treatment terminated.

The written material may also describe that delivery of the formulationof the interferon intended for short-term administration is byinjection, infusion, inhalation, oral or transdermal administration. Thepreferred embodiment is by injection or infusion and the most preferredis by injection. Warnings, precautions, and contraindications should bedescribed.

EXAMPLE OF DOSIMETRY PROTOCOL

In treating a disease such as hepatitis C, antiviral effects fromadministration of an interferon may become obvious within hours orwithin a few days. Accordingly, in order to begin the assessment of thesafety, tolerability, and effectiveness of the short-term formulation ofthe interferon, it is informative to utilize a short-term dosimetryprotocol to assess antiviral effects. This protocol is a furtherelucidation of the invention.

At baseline (preferably within 1 hour prior to the initiation of dosingwith the short-term formulation) and at, preferably, 8 and 14 days afterdosing has begun, chemistry, hematology, and liver function testing areperformed. Samples for hepatitis C viral ribonucleic acid levels (HCVRNA) testing are then obtained at baseline and again preferably at 2, 4,7,10, 14, 19 and 24 hours after dosing on Day 1 (the initial dose ofinterferon); at 5 and 10 hours after dosing on Day 2, and immediatelyprior to the daily omega interferon dose on Days 3, 4, 5, 6, 8, 10, 12and 14 of dosing. Similar tests can then be performed, if required, at2-4 weeks intervals while viral response and safety and tolerability arebeing assessed while the short-term formulation is being administered.Most preferably, this assessment is performed using omega interferon.

Responsiveness to treatment can be assessed by various parameters,ranging from

-   -   a lack of detectable HCV RNA (viral load is below the lower        limit of detectability for the assay being used) or    -   a decrease in HCV RNA level to less than a preselected        percentage of baseline viral load, e.g., 50% of pretreatment        level,    -   a decrease in a liver enzyme such as alanine amino transferase        (ALT) to normal or to less than a preselected percentage of        baseline viral load, e.g., 50% of pretreatment level or    -   histopathological changes as assessed by liver biopsy.

Dosing at different levels and for variable periods of time may benecessary to establish an adequate safety, tolerability, and efficacyprofile (i.e. maximize therapeutic response and minimizing adverseeffects) for the short-term formulation and to enhance the predictivepower of the information acquired during the use of the short-termformulation. The duration of such assessments could be as short as oneday but preferably such assessments are made for at least one week, morepreferably for two to four weeks, and most preferably for four to eightweeks.

Assessment of antiviral response or measurement of changes in liverfunction tests may necessary in order to select a dosage (i.e.dose-level or dose-rate level) intended for long term administrationfrom a long-term delivery system. Very rapid assessment of antiviraleffects in patients with hepatitis C can now be accomplished asdescribed below. The invention is not limited by the particular viralpharmacodynamic model, doses, time or time intervals, or factors to beconsidered in the application of a particular model. Although assessmentof antiviral response is preferable to occur within no more than days ora few weeks of initiating long-term therapy, the current inventionencompasses the possibility that initial antiviral assessment may haveoccurred weeks, months, or possibly a year or more prior to theinitiation of long-term treatment.

DESCRIPTION OF MODELING OF VIRAL KINETICS

To model the kinetics of hepatitis C viral kinetics during treatmentwith omega interferon, we have used a standard model of viral infectiondescribed by the differential equations:dT/dt=s−dT−(1−η)βVTdI/dt=(1−η)βVT−δIdV/dt=(1−ε)pI−cV

where the terms are defined as shown in the table below: Definition ofTerms T Number of target cells t Time d Rate constant for death oftarget cells s Rate of production of target cells η Fractional reductionin de novo rate of infection of target cells β Rate constant for de novoinfection of target cells V Viral load I Number of productively infectedcells δ Rate constant for death of infected cells ε Fractional reductionin production of virions by infected cells p Rate of production ofvirions by infected cell c Rate constant for clearance of virions

If it is assumed that initially η=0 and that the number of productivelyinfected cells remains relatively constant for the first two days oftherapy, then the viral load (V) at time t, V(t), isV(t)=V ₀[1−ε+εexp(−c(t−t ₀))]

The parameters ε and c can be estimated, among others, for each patientusing nonlinear regression analysis to fit the above equation to the HCVRNA levels measured for the 48 hours after initiation of omegainterferon dosing. Using those parameter values calculated for eachpatient and assuming the number of target cells remains relativelyconstant over the two weeks of therapy, nonlinear regression analysiscan also be used to estimate the parameter δ for each patient using theequationV(t)=V ₀ {Aexp[λ₁(t−t ₀)]+(1−A)exp[−λ₂(t−t ₀)]}whereλ_(1,2)=½{(c+δ)±[(c−δ)²+4(1−ε)cδ] ^(1/2)}A=(εc−λ ₂)/λ₁−λ₂)

Fitting these equations to the data obtained in clinical testing withtwo different doses of omega interferon in patients withalpha-interferon resistant hepatitis C, we have estimated the followingvalues for the key parameters of antiviral effect, ε and C. Mean ValueParameter 15 □g/day (n = 7) 30 □g/day (n = 4) ε .75 .78 C 7.25 day⁻¹3.10 day⁻¹

These findings indicate that, on average, there is a 75-78% reduction invirion production by infected cells and that the rate constant forvirion clearance increases with increasing dose, i.e., that the timerequired for a given clearance level is decreasing.

The analysis of data from a clinical study of the type described inpatients with viral hepatitis C can estimate the activity of severaldoses of interferon and the time-course and mechanism(s) of antiviralactivity. The model parameter measuring initial antiviral activity is ε,the fractional reduction in the production of virions by infected cells.For any group of patients treated at one dose level, it is possible todetermine the group range, median, and mean (with 95% confidenceinterval by Normal approximation) for ε. The same group of patients canthen be treated at a different dose level and the antiviral effectscompared within and between patients. The data from this type of studycan be used to guide the selection of dose(s) to be administered duringlong-term treatment.

It is possible to perform the multiple pairwise comparisons of εcalculated for the multiple dosing groups of patients. For each pair ofgroups it is possible to report the difference in mean ε (with 95%confidence interval by Normal approximation) and median ε (with 95%confidence intervals).

As an additional evaluation of possible antiviral activity, it ispossible to examine the percent change in serum HCV RNA, alanine aminotransferase (ALT) and aspartate amino transferase (AST) from baseline tothe end of therapy for each patient, as well as the group medians andmeans (with 95% confidence intervals by Normal approximation).

The relationship baseline ALT levels and initial viral load to E andrelationship of baseline ALT and initial viral load to δ can be assessedusing appropriate statistics. All changes in physical examinations, alladverse events and any significant changes in laboratory parameters canbe assessed and compared, if need be, between different dosing groups orbetween different dose levels or dose rates for the same patient.

Such effects after administration of a short-term formulation can bedetermined over a short period of time measured in hours to days tolonger periods of time, measured in days to weeks or, if necessary, evenweeks to months before selecting the long-term dose or dose-rate andchanging from administering the (first) short-term formulation toadministering the (second) long-term formulation, whether a singleformulation or a combination of modules.

In one embodiment, dosing with an interferon is performed at intervalsranging from 2 to 24 hours in order to establish a target steady stateblood or tissue level. Dosing at this frequency may be maintained for 1to 3 or more days after which dosing frequency may be reduced at thediscretion of the health care provider.

The object of the administration of the short-term formulation is todetermine a generally effective and generally safe and tolerated dose,i.e. to improve the therapeutic index. This object can be achieved bystep-wise adjustments in the dose of interferon delivered with theshort-term formulation. Dosing can be initiated at what is believed tobe a low or even ineffective dose and escalated at regular or irregularintervals. Dosing escalation can continue until a poorly tolerated doseis reached or until a maximally effective dose is reached (based onantiviral effects and desirable changes in liver function tests). Thendosing can be stabilized or reduced moderately and then stabilized totest the effectiveness and tolerability of the chosen dose level ordose-rate. See FIG. 5 for a visual representation of this sequence ofevents.

The dose to be delivered with the long-term formulation can be adjustedto match the most generally effective and generally safe and tolerateddose as determined by use of the short-term formulation during theshort-term formulation treatment period. To maximize the utility of thedata from use of the short-term formulation, the dose, dose interval anddosing frequency of the short-term formulation is preferably adjusted toproduce a drug delivery profile that matches as closely as possible thatwhich is to be delivered by the long-term formulation.

The following examples of the present invention are provided toillustrate the invention in more detail. The examples are to be taken asillustrative only, without limiting the scope of the invention.

EXAMPLE 1

Omega Interferon in a Short-Term Formulation Followed by OmegaInterferon in a Long-Term Formulation Suitable for Use in anImplantable, Non-Erodible Drug Delivery Formulation

Preparation and Administration of Omega Interferon in a Short-TermFormulation

Omega interferon is produced by standard genetic engineering techniquesin E. coli bacteria or in mammalian Chinese hamster ovary cells. Suchtechniques are further described for interferons generally in U.S. Pat.No. 4,727,138 and more specifically for omega interferon in U.S. Pat.No. 5,120,832 and U.S. Pat. No. 5,231,176. The interferon is thenpurified and used immediately or frozen and then subsequently thawed foruse. The interferon may be lyophilized with appropriate stabilizers forsubsequent reconstitution with water-for-injection or other suitablesolvent or the interferon may be prepared for use initially as a liquidformulation.

For a lyophilized preparation of omega interferon 33 μg of omegainterferon (measured by the amount of protein present) is prepared alongwith, by way of example, human serum albumin 25% (5 mg), potassiumchloride (0.2 mg), potassium dihydrogen phosphate (0.2 mg), sodiumchloride (8.0 mg). This lyophilized preparation is maintained at 2-8° C.and then reconstituted with 1 mL of sterile water-for-injection. Asknown to those skilled in the art, other formulations are possible.

For a liquid formulation of an interferon, the interferon is dissolvedin 1 mL sterile water-for-injection which can also contain sodiumchloride (7.5 mg), sodium phosphate dibasic (1.8 mg), sodium phosphatemonobasic (1.3 mg), edetate disodium (0.1 mg), polysorbate 80 (0.1 mg),and m-cresol (1.5 mg) as a preservative, among other excipients known tothose skilled in the art.

This short-term formulation is then administered by subcutaneous orintramuscular injection or by bolus intravenous injection or byinfusion, preferably by subcutaneous injection.

A formulation for long-term use is dependent upon the long-term deliveryformulation. For a non-erodible implant, a suitable formulation will bestable at the body temperature of warm-blooded animals for the durationof the dose contained by or within the system. It has been demonstratedthat an interferon remains chemically stable and active in aperfluorocarbon solvent such as perfluorodecalin. Non-erodibleimplantable systems suitable for use in delivery of a long-termformulation are described in U.S. Pat. Nos. 4,976,966, 5,112,614,5,660,847, 5,728,396, 5,985,305, 6,113,938, which are incorporatedherein by reference.

After determination of a safe, tolerated and effective dose using thefirst, short-term formulation, preferably wherein the selection was madeby replicating the pharmacokinetics of delivery of the long-term systemusing the short-term formulation and appropriately selected doses anddosing intervals, the long-term dose and dose-rate are selected. Oneskilled in the art will know that it is then necessary only to load thelong-term delivery system with the predetermined total dose.

Alternatively, a generally safe and effective total dose per unit timeis established for a population of animals with an interferon-responsivedisease using the short-term formulation. The most preferred interferonis omega interferon. The most preferred interferon-responsive disease isviral hepatitis C. The unit of time may be conveniently selected fromday, week, month, or quarter-year.

The preferred unit of time is chosen with regard to factors thatcomprise the maximal delivery period of the selected long-term deliverysystem, the most reliable delivery period for a selected long-termdelivery formulation, the particular interferon, the stability of theinterferon in the long-term formulation.

For the convenience of humans to be treated with the current invention,the preferred unit of time for the drug to be delivered over thelong-term in the long-term formulation is either the month orquarter-year and the most preferred is the quarter-year. This gives thephysician an opportunity to review progress in the patient and tocontinue long-term treatment as needed.

Unit Dose and Fractional Unit Modules

The total dose for the selected unit of time is then selected as the“unit-dosage” for the long-term delivery system. In the case of animplantable, non-erodible delivery system, the system may also be loadedwith fractional unit doses. In the case of bio-erodible systems, eitherlesser volumes of the bio-erodible system are utilized or fractionalamounts of the unit-dose are loaded into or onto the system.

In the case of viral hepatitis C, the preferred unit-dose perquarter-year is 300-8100 μg of omega-IFN. A more preferred unit-dose perquarter-year is 300-5040 μg and the most preferred unit-dose perquarter-year is 630-2520 μg.

Those skilled in the art will understand that with a unit-dose and, ifdesired, one or more fractional unit-dose module, the long-term dose canbe individualized for an animal with an interferon-responsive disorderand to achieve a practical matching of the long-term dose with the dosedetermined from the previous use of the short-term formulation.

Those skilled in the art will recognize, however, that for practicalpurposes in the therapy of interferon-responsive disorders, a range ofunit-doses will be safe, tolerated, and effective, thus minimizing theneed for excessively numerous fractional unit-dose modules. Moreover, ifthe unit-dose is well chosen and based on data from a sufficiently largenumber of humans with interferon-responsive disorders, then it ispossible to minimize further the need for a large number of long-termunit-dosage formulations or fractional unit-dose modules.Notwithstanding the foregoing, with knowledge of the results of the useof the short-term formulation, a unit-dose system (i.e. the long-termformulation) used with or without one or more fractional unit-dosemodules provides great flexibility in the selection of dose,individualization of long-term dosing and optimization of long-termdosing.

EXAMPLE 2

Omega Interferon in a Short-Term Formulation Followed by OmegaInterferon in a Long-Term Formulation Suitable for Use in an Implantableor Injectable Erodible or Dispersible Drug Delivery System

Omega interferon is prepared for short-term use as described in EXAMPLE1.

Erodible or dispersible implantable or injectable drug delivery systemssuitable for use in the long-term delivery of an interferon, includingomega interferon, include such systems as described in U.S. Pat. No.5,543,156, which is incorporated herein by reference, as well as in U.S.Pat. Nos. 5,529,914, 5,858,746, and 6,129,761, which are alsoincorporated herein by reference.

Those skilled in the arts will recognize that the current invention canbe utilized to optimize or improve the long-term treatment ofwarm-blooded animals with any interferon-responsive condition and withany interferon or interferon-like molecule suitable for short-termformulation or suitable for long-term formulation with an appropriatelychosen long-term delivery system, and whether employed as monotherapy oras part of a combination therapy regimen.

All articles, patents and other information cited herein areincorporated by reference for all purposes.

1-64. (canceled)
 65. A method of treating an interferon-responsivedisorder in a warm-blooded animal, comprising administering to theanimal via an internally implanted pump that is not externallyprogrammed an amount of an interferon determined from short-termadministration of the same or a different interferon to be suitable totreat the disorder.
 66. The method of claim 65, wherein administrationvia the pump and the short-term administration overlap.
 67. The methodof claim 65, wherein administration via the pump and the short-termadministration do not overlap.
 68. The method of claim 65, wherein thereis a period of at least a few hours without treatment betweenadministration via the pump and the short-term administration.
 69. Themethod of claim 65, wherein there is a period of at least one daywithout treatment between administration via the pump and the short-termadministration.
 70. The method of claim 65, wherein administration viathe pump occurs at least one day subsequent to cessation of theshort-term administration.
 71. The method of claim 65, wherein there isa period of one month or more without treatment between administrationvia the pump and the short-term administration.
 72. The method of claim65, wherein there is a period of six months or more without treatmentbetween administration via the pump and the short-term administration.73. The method of claim 65, wherein there is a period of nine months ormore without treatment between administration via the pump and theshort-term administration.
 74. The method of claim 65, wherein there isa period of twelve months or more without treatment betweenadministration via the pump and the short-term administration.
 75. Themethod of claim 65, wherein the short-term formulation of interferon isselected from natural or recombinant alpha, beta, consensus, gamma,leukocyte, omega, or tau interferon or versions thereof to whichpolyethylene glycol or a polyethylene glycol-fatty acid moiety has beenattached by covalent or non-covalent bonding, or mixtures thereof. 76.The method of claim 65 wherein the interferon administered via the pumpis selected from naturally occurring or recombinant omega interferon, orversions thereof to which polyethylene glycol or a polyethyleneglycol-fatty acid moiety has been attached by covalent or non-covalentbonding, or mixtures thereof.
 77. The method of claim 65, wherein theinterferon-responsive disease is selected from viral hepatitis C, viralhepatitis B, viral hepatitis D, condyloma accuminata, hairy cellleukemia, malignant melanoma, multiple myeloma, follicular lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic myelogenousleukemia, basal cell carcinoma, mycosis fungoides, carcinoid syndrome,superficial bladder cancer, renal cell cancer, colorectal cancer,laryngeal papillomatosis, actinic keratosis, Kaposi's sarcoma, multiplesclerosis, chronic granulomatous disease, pulmonary fibrosis, andtuberculosis.
 78. The method of claim 65, wherein administration via thepump occurs over a period of at least approximately one month.
 79. Themethod of claim 65, wherein administration via the pump occurs over aperiod of at least approximately a quarter year.
 80. The method of claim65, wherein administration via the pump occurs over a period ofapproximately a year.
 81. A method for individualizing doses of aninterferon in the treatment of interferon responsive disorders in awarm-blooded animal, comprising administering to an individual animalvia an internally implanted pump that is not externally programmed anamount of an interferon determined from short-term administration of thesame or a different interferon in a plurality of animals to be suitableto treat the disorder.
 82. The method of claim 81, wherein theshort-term formulation of interferon is selected from natural orrecombinant alpha, beta, consensus, gamma, leukocyte, omega, or tauinterferon or versions thereof to which polyethylene glycol or apolyethylene glycol-fatty acid moiety has been attached by covalent ornon-covalent bonding, or mixtures thereof
 83. The method of claim 81wherein the interferon administered via the pump is selected fromnaturally occurring or recombinant omega interferon, or versions thereofto which polyethylene glycol or a polyethylene glycol-fatty acid moietyhas been attached by covalent or non-covalent bonding, or mixturesthereof.
 84. The method of claim 81, wherein the interferon-responsivedisease is selected from viral hepatitis C, viral hepatitis B, viralhepatitis D, condyloma accuminata, hairy cell leukemia, malignantmelanoma, multiple myeloma, follicular lymphoma, non-Hodgkin's lymphoma,cutaneous T-cell lymphoma, chronic myelogenous leukemia, basal cellcarcinoma, mycosis fungoides, carcinoid syndrome, superficial bladdercancer, renal cell cancer, colorectal cancer, laryngeal papillomatosis,actinic keratosis, Kaposi's sarcoma, multiple sclerosis, chronicgranulomatous disease, pulmonary fibrosis, and tuberculosis.